Differentiating Mild Papilledema and Buried Optic Nerve Head Drusen Using Spectral Domain Optical Coherence Tomography Kaushal M. Kulkarni, MD,1,2 Joshua Pasol, MD,2 Potyra R. Rosa, MD,2 Byron L. Lam, MD2 Purpose: To evaluate the clinical utility of spectral domain optical coherence tomography (SD-OCT) in differentiating mild papilledema from buried optic nerve head drusen (ONHD). Design: Comparative case series. Participants: Sixteen eyes of 9 patients with ultrasound-proven buried ONHD, 12 eyes of 6 patients with less than or equal to Frisén grade 2 papilledema owing to idiopathic intracranial hypertension. Two normal fellow eyes of patients with buried ONHD were included. Methods: A raster scan of the optic nerve and analysis of the retinal nerve fiber layer (RNFL) thickness was performed on each eye using SD-OCT. Eight eyes underwent enhanced depth imaging SD-OCT. Images were assessed qualitatively and quantitatively to identify differentiating features between buried ONHD and papilledema. Five clinicians trained with a tutorial and masked to the underlying diagnosis independently reviewed the SD-OCT images of each eye to determine the diagnosis. Main Outcome Measures: Differences in RNFL thickness in each quadrant between the 2 groups and diagnostic accuracy of 5 independent clinicians based on the SD-OCT images alone. Results: We found no difference in RNFL thickness between buried ONHD and papilledema in any of the 4 quadrants. Diagnostic accuracy among the readers was low and ranged from 50% to 64%. The kappa coefficient of agreement among the readers was 0.35 (95% confidence interval, 0.19e0.54). Conclusions: We found that SD-OCT is not clinically reliable in differentiating buried ONHD and mild papilledema. Ophthalmology 2014;121:959-963 ª 2014 by the American Academy of Ophthalmology.

Optic nerve head drusen (ONHD) are acellular, calcific deposits that typically occur in small, crowded optic discs with abnormal vasculature.1 When ONHD are on the optic disc surface, they usually can be easily visualized as refractile, beige, rounded deposits on ophthalmoscopy. However, when the drusen are buried within the optic nerve head, the optic discs may seem to be elevated bilaterally, mimicking optic disc edema owing to papilledema or another process causing bilateral disc elevation. The ability to accurately diagnose buried ONHD and distinguish it from true papilledema is often difficult yet critical. This is because buried ONHD usually follow a benign natural course, whereas papilledema requires an emergent neurologic workup for potentially life-threatening conditions. Buried ONHD can be identified using various diagnostic modalities, including fundus autofluorescence, fluorescein angiography, and computed tomography. Currently, B-scan ultrasonography seems to be the most reliable method.2 Unfortunately, B-scan ultrasonography may not be readily and widely available in all clinical settings, and the diagnosis of buried ONHD requires a skilled ultrasonographer and interpreter, particularly in subtle cases. Optical coherence tomography (OCT), on the other hand, is widely available and has been proposed as a potential diagnostic tool in the diagnosis of ONHD. Several studies have  2014 by the American Academy of Ophthalmology Published by Elsevier Inc.

attempted to describe qualitatively the OCT findings in cases of ONHD, including changes in the retinal nerve fiber layer (RNFL) thickness,3e8 and a recent study9 compared enhanced depth imaging OCT (EDI-OCT) to B-scan ultrasonography in the detection of ONHD. More important, several authors have attempted to assess the utility of OCT in differentiating cases of optic disc edema from ONHD.9e13 These studies have included eyes with disc swelling of varying etiologies other than elevated intracranial pressure, such as ischemic optic neuropathy, uveitis, optic neuritis, diabetic papillopathy, and central retinal vein occlusion. However, in our clinical experience, disc swelling owing to these other conditions is rarely confused with ONHD. These studies also have included eyes with clinically visible ONHD, which usually can be accurately identified by careful funduscopic examination and do not require further workup. In the majority of patients, the main diagnostic challenge lies in differentiating buried ONHD from mild papilledema. The purpose of this study was to determine if spectral domain OCT (SD-OCT) can be used to realistically differentiate these 2 conditions in clinical practice.

Methods The study was approved by the institutional review board of the University of Miami Miller School of Medicine and performed in ISSN 0161-6420/14/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.10.036

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Ophthalmology Volume 121, Number 4, April 2014 compliance with the tenets of the Declaration of Helsinki and the Health Insurance Portability and Accountability Act. Informed consent was obtained from all patients. Patients with ultrasound-proven buried ONHD and patients with mild (grade 2 or less using the Frisén staging scheme12) disc swelling owing to papilledema were recruited from the neuro-ophthalmology service. All patients in the papilledema group met the modified Dandy criteria13 for idiopathic intracranial hypertension, including unremarkable magnetic resonance imaging and magnetic resonance venography of the brain and cerebrospinal fluid pressure of 23 cm H2O in the lateral decubitus position. In addition, all patients in the papilledema group underwent B-scan ultrasonography with no identifiable ONHD. Patients with any visible ONHD were excluded from the study. Two patients with both buried ONHD and coexisting papilledema were excluded. Patients were excluded if they had any coexisting retinal or other optic nerve pathology. Patients were also excluded if they had significant systemic disease, including hypertension, diabetes, and autoimmune disease. All patients underwent a complete neuro-ophthalmic examination, automated visual field testing (Humphrey Swedish interactive thresholding algorithm), color fundus photographs, autofluorescence of the optic discs, and B-scan ultrasonography by a certified, professional ultrasonographer.

OCT Protocol The optic nerve heads of all subjects were assessed with the Spectralis SD-OCT (Heidelberg Engineering, Heidelberg, Germany) and the Cirrus High Density SD-OCT (Carl Zeiss Meditec, Dublin, CA) on each eye. For the Spectralis SD-OCT, the device was set to image a 1015 rectangle to obtain a vertical raster scan centered on the optic disc in automatic retinal tracking mode. This rectangle was scanned with 48 sections, and each section had 25 frames averaged. For the Cirrus SD-OCT, a cube scan consisting of 512 A-scans  128 B-scans centered on the optic disc, a 5-line raster scan centered on the optic disc, and RNFL thickness analysis were performed on each eye. In addition, 4 eyes with buried ONHD and 4 eyes with papilledema underwent Spectralis EDI-OCT. The device was set to image a 1015 rectangle to obtain a vertical raster scan centered on the optic disc in EDI mode. This rectangle was scanned with 97 sections, and each section had 20 frames averaged. All of the patients in the buried ONHD group were evaluated with OCT on the same day of diagnosis. In the papilledema group, all patients were evaluated with OCT after confirmation of elevated opening cerebrospinal fluid pressure using a diagnostic lumbar puncture. All patients in the papilledema group were receiving treatment with acetazolamide at the time of OCT evaluation. Some patients in the group had demonstrated improvement of their initial level of optic disc edema at the time of OCT evaluation. However, no patient in the group had Frisén grade 3 disc swelling at baseline or at any time during their initial diagnosis or follow-up at our institution.

OCT Assessment and Statistical Analysis The OCT images were assessed qualitatively to identify distinguishing features between eyes with papilledema and buried ONHD. Mean RNFL thickness in all 4 quadrants was compared between the 2 groups using the Cirrus OCT data in the right eye. In addition, OCT images were evaluated by 5 independent, experienced clinicians (1 corneal specialist, 1 retinal specialist, 1 glaucoma specialist, and 2 neuro-ophthalmologists). The clinicians (readers) were initially given a tutorial with representative OCT

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images of both buried ONHD and papilledema based on the qualitative analysis that was done to identify morphologic characteristics of the 2 groups. The readers then were given the complete set of OCT images through the optic nerve of each eye in the study and were masked to the underlying diagnosis as well as patient identifiers. To make the assessment clinically relevant, they then were asked to choose one of the following management options based on the OCT images through each eye: 1. Clearly identifiable buried ONHD. I would not perform any further diagnostic workup. 2. Optic disc edema (papilledema) without evidence of buried ONHD. I would proceed with further diagnostic workup. 3. Normal-appearing optic nerve on OCT. I would not perform any further diagnostic workup. The accuracy of each reader was calculated, and the interreader agreement was evaluated using a kappa coefficient of agreement, including a 95% confidence interval.

Results Patient demographics are shown in Table 1.

Qualitative Analysis In several patients with buried ONHD, a hyperreflective mass causing focal, irregular elevation of the optic nerve head and adjacent retina was identified on SD-OCT (Figure 1). In several patients with papilledema, optic disc elevation with a smooth contour was identified on SD-OCT, without any underlying hyperreflective bodies (Figure 2). However, these findings were variable. A specific, focal, hyperreflective mass was absent in many of the drusen cases. Several papilledema eyes showed hyperreflective areas underneath the optic disc that mimicked ONHD (Figure 3).

Quantitative Analysis We found no difference in RNFL thickness between the 2 groups in any of the 4 quadrants (Table 2). Using the SD-OCT images alone for diagnosis, the accuracy of the 5 readers ranged from 50% to 64%. The kappa coefficient of agreement among the readers was 0.35 (95% confidence interval, 0.19e0.54). Overall, 41% to 75% of eyes with papilledema were mistaken as buried ONHD or normal, whereas 13% to 56% of eyes with buried ONHD were mistaken as papilledema or normal.

Discussion Differentiating buried ONHD from papilledema is an important yet difficult diagnostic challenge. Several studies Table 1. Patient Demographics Characteristic

Buried ONHD

Papilledema

P

No. of patients No. of eyes Female sex, SD (%) Mean (SD) age (yr)

9 16 5 (55.5) 19.8 (12.8)

6 12 6 (100) 27.8 (21.4)

0.1* 0.9y

ONHD ¼ optic nerve head drusen; SD ¼ standard deviation. *Fisher exact test. y t Test.

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Figure 1. Buried optic nerve head drusen. (A) Right and (B) left eyes demonstrating a focal, round, hyperreflective mass causing nasal optic disc elevation with an irregular contour (arrows). Thin arrow indicates raster scan through optic nerve.

Figure 2. Papilledema. (A) Right and (B) left eyes demonstrating a smooth elevation of the optic disc without underlying hyperreflective bodies causing elevation.

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Figure 3. Papilledema. Irregular optic nerve contour with hyperreflective areas mimicking buried optic nerve head drusen.

have attempted to describe the OCT findings in ONHD. These studies have reported a wide variability in the reflectivity, shape, size, and location of the drusen on OCT. Some authors5e7 have described elevation of the optic nerve head and adjacent retina with round, optically empty spaces and a discrete boundary corresponding with the areas of the drusen, with anterior and posterior lines of reflectance. The hyporeflective nature was thought to represent the homogeneous nature of the drusen. The EDI-OCT images revealed signal-poor regions surrounded by short, hyperreflective bands or isolated/clustered hyperreflective bands without a signal-poor core.9 Other authors11 have found that ONHD can be visualized as a focal hyperreflective mass with clear margins posterior to the outer plexiform and outer nuclear layers. In our study, we found that buried ONHD, when identifiable on OCT, appeared as a focal, round, hyperreflective mass causing optic nerve head elevation. Most authors agree that optic nerve head elevation with a smooth internal contour is seen in eyes with optic disc edema. In addition, OCT analysis has been used to characterize the morphology of the peripapillary retinal pigment epithelium and Bruch’s membrane in cases of papilledema. Kupersmith et al14 reported inward deflection of the retinal pigment epithelium and Bruch’s membrane layer on OCT in eyes with papilledema, presumably owing to biomechanical forces in the retrolaminar subarachnoid space. However, in our cases of mild optic disc elevation from papilledema, we did not observe this phenomenon; instead, in several cases of mild papilledema, we observed nonspecific Table 2. Mean (Standard Deviation) Retinal Nerve Fiber Layer Thickness by Quadrant Quadrant Superior Nasal Inferior Temporal

Buried ONHD 137.2 77.2 139.5 77.1

(48.2) (20.3) (28.0) (12.6)

ONHD ¼ optic nerve head drusen. *t Test.

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Papilledema 177.6 132.8 205.8 83.1

(81.4) (84.2) (113.5) (15.5)

P* 0.25 0.17 0.22 0.42

hyperreflective areas underneath the optic nerve (Figure 3) that were easily confused with drusen; the etiology of these hyperreflective areas is unclear. Quantitatively, several studies12,13,15,16 have reported a difference in measures of the subretinal hyporeflective space and/or RNFL thickness in different quadrants between eyes with disc swelling of various etiologies and eyes with visible or buried ONHD. We found no difference in RNFL thickness in any quadrant between eyes with mild papilledema and eyes with buried ONHD. Furthermore, in our study, the ability of 5 clinicians (including 2 neuro-ophthalmologists) to differentiate buried ONHD from mild papilledema using the OCT images alone was poor, as was the interreader agreement. In particular, several eyes with papilledema were mistaken for buried ONHD or normal, suggesting that a potentially life-threatening condition may be missed. The difficulty of using OCT to differentiate between mild papilledema and congenitally crowded and anomalous optic nerves has been demonstrated by Karam et al.17 Similarly, we demonstrate the difficulty of using OCT to differentiate between mild papilledema and buried ONHD. Therefore, in cases where the differentiation between these 2 conditions is uncertain, B-scan ultrasonography should be performed if available, and if no calcified buried ONHD are identified, one should proceed with appropriate neurologic workup as clinically indicated. Limitations of this study include the small sample size, lack of widely accepted and standardized morphologic criteria for identifying buried ONHD and papilledema on OCT, and difference in timing of the OCT evaluation between the study groups (ie, initial visit in the buried ONHD group vs follow-up period while receiving treatment in the papilledema group). At this time, whether or not ONHD appear as a hyperreflective or hyporeflective space on OCT remains unclear.18 The variable appearance of ONHD on OCT may be related to variable composition and anatomic location. It is likely that surface drusen will appear as a hyporeflective space on OCT owing to a shadowing effect, with anterior and posterior lines of reflectance, whereas buried drusen, as shown in this study, will appear as a hyperreflective mass. To the best of our knowledge, this is the first study to investigate specifically the role of SD-OCT in differentiating

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mild papilledema and buried ONHD in a clinical setting. This remains an important but difficult diagnostic challenge. At the present time, OCT alone is unreliable in differentiating these 2 conditions. Acknowledgments. The authors gratefully acknowledge Barry K. Lipson, Eric J. Linebarger, and Ann Lopez for their contributions to the study, as well as William J. Feuer for his assistance with the statistical analysis.

References 1. Lam BL, Morais CG Jr, Pasol J. Drusen of the optic disc. Curr Neurol Neurosci Rep 2008;8:404–8. 2. Kurz-Levin MM, Landau K. A comparison of imaging techniques for diagnosing drusen of the optic nerve head. Arch Ophthalmol 1999;117:1045–9. 3. Roh S, Noecker RJ, Schuman JS, et al. Effect of optic nerve head drusen on nerve fiber layer thickness. Ophthalmology 1998;105:878–85. 4. Katz BJ, Pomeranz HD. Visual field defects and retinal nerve fiber layer defects in eyes with buried optic nerve drusen. Am J Ophthalmol 2006;141:248–53. 5. Wester ST, Fantes FE, Lam BL, et al. Characteristics of optic nerve head drusen on optical coherence tomography images. Ophthalmic Surg Lasers Imaging 2010;41:83–90. 6. Murthy RK, Storm L, Grover S, et al. In-vivo high resolution imaging of optic nerve head drusen using spectral-domain optical coherence tomography. BMC Med Imaging [serial online] 2010;10:11. Available at: http://www.biomedcentral. com/1471-2342/10/11. Accessed October 21, 2013. 7. Slotnick S, Sherman J. Buried disc drusen have hypo-reflective appearance on SD-OCT [report online]. Optom Vis Sci 2012;89:E704–8. Available at: http://journals.lww.com/ optvissci/toc/2012/05000. Accessed October 21, 2013.

8. Lee KM, Woo SJ, Hwang JM. Morphologic characteristics of optic nerve head drusen on spectral-domain optical coherence tomography. Am J Ophthalmol 2013;155:1139–47. 9. Merchant KY, Su D, Park SC, et al. Enhanced depth imaging optical coherence tomography of optic nerve head drusen. Ophthalmology 2013;120:1409–14. 10. Johnson LN, Diehl ML, Hamm CW, et al. Differentiating optic disc edema from optic nerve head drusen on optical coherence tomography. Arch Ophthalmol 2009;127:45–9. 11. Lee KM, Woo SJ, Hwang JM. Differentiation of optic nerve head drusen and optic disc edema with spectral-domain optical coherence tomography. Ophthalmology 2011;118: 971–7. 12. Sarac O, Tasci YY, Gurdal C, Can I. Differentiation of optic disc edema from optic nerve head drusen with spectral-domain optical coherence tomography. J Neuroophthalmol 2012;32: 207–11. 13. Flores-Rodríguez P, Gili P, Martín-Ríos MD. Sensitivity and specificity of time-domain and spectral-domain optical coherence tomography in differentiating optic nerve head drusen and optic disc oedema. Ophthalmic Physiol Opt 2012;32: 213–21. 14. Kupersmith MJ, Sibony P, Mandel G, et al. Optical coherence tomography of the swollen optic nerve head: deformation of the peripapillary retinal pigment epithelium layer in papilledema. Invest Ophthalmol Vis Sci 2011;52: 6558–64. 15. Frisén L. Swelling of the optic nerve head: a staging scheme. J Neurol Neurosurg Psychiatry 1982;45:13–8. 16. Smith JL. Whence pseudotumor cerebri? J Clin Neuroophthalmol 1985;5:55–6. 17. Karam EZ, Hedges TR. Optical coherence tomography of the retinal nerve fibre layer in mild papilloedema and pseudopapilloedema. Br J Ophthalmol 2005;89:294–8. 18. Slotnick S, Sherman J. Disc drusen [letter]. Ophthalmology 2012;119:652. author reply 652-3.

Footnotes and Financial Disclosures Originally received: July 11, 2013. Final revision: October 3, 2013. Accepted: October 25, 2013. Available online: December 9, 2013. Manuscript no. 2013-1143. 1 Department of Ophthalmology, Sharp Rees-Stealy Medical Group, San Diego, California. 2

Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida.

Supported by National Institute of Health Center grant P30-EY014801 and an unrestricted grant from Research to Prevent Blindness, New York, New York. The funding organization had no role in the design or conduct of this research. Correspondence: Kaushal M. Kulkarni, MD, Sharp Rees-Stealy Medical Group, 10243 Genetic Center Drive, San Diego, CA, 92110. E-mail: kaushal.kulkarni@ gmail.com.

Financial Disclosures: The authors have no proprietary or commercial interest in any of the materials discussed in this article.

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Differentiating mild papilledema and buried optic nerve head drusen using spectral domain optical coherence tomography.

To evaluate the clinical utility of spectral domain optical coherence tomography (SD-OCT) in differentiating mild papilledema from buried optic nerve ...
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